The importance of the placenta in determining pregnancy outcome is undeniable, yet access to this unique organ is largely limited to post-delivery when it has completed its function and exceeded its lifespan. An adequate understanding of placental development in both normal and abnormal pregnancies is critical to identify patients at risk for complications, to determine biomarkers for at risk pregnancies, to develop targeted therapeutics for pregnancies at risk, and to appropriately stratify patients in clinical trials. A fundamental limitation in our understanding of placental function and development is our inability to quantitatively assess basic functional outputs such as blood flow and oxygenation. Our proposal seeks to overcome these limitations by utilizing a magnetic resonance imaging (MRI)-based approach. Specifically, our multidisciplinary group has designed a MRI data acquisition and analysis protocol that incorporates the unique vascular structural organization of the primate placenta, which we believe is critical for converting non-invasive imaging data into quantitative anatomical and physiological parameters of relevance to placenta function and mechanisms of impairment. This new approach utilizes endogenous contrast to quantify maternal perfusion of the placenta, has been validated in a pre-clinical animal model and is now ready to be transitioned to human application. The objective of this proposal is therefore to optimize the endogenous contrast MR acquisition protocols for human pregnancy, adapt the 3D analysis tools we previously developed for analyzing contrast-dependent data for modeling of non-contrast perfusion maps in humans, and ascertain fundamental data that will establish the normal variance of placental perfusion in pregnant women longitudinally across gestation in normal and at-risk human pregnancies, focusing on smoking as an environmental perturbation of placental function. We are proposing a longitudinal prospective cohort study of 300 pregnant women across two sites: OHSU and the University of Utah. All study participants will undergo three placental MRI scans across gestation (12-16, 26-28 and 32-34 weeks gestation) and placental tissue will be collected at the time of delivery. Subjects will be recruited based on selection criteria in three cohorts: 1) non-smokers, 2) smokers and 3) high risk for adverse pregnancy outcome. Our scientific approach will allow us to generate data that will demonstrate the normal variance of placental perfusion in pregnant women across gestation. Application of our endogenous contrast MRI protocol in women at high risk for vascular compromise (i.e., smokers and those with a prior history of placental insufficiency) will allow us to test the sensitivity and specificity of this new techniqu for predicting adverse clinical outcomes. Successful development of these tools will significantly advance non-invasive imaging of placental function by creating a method that quantitatively determines placental perfusion while preserving the spatial and physiologic characteristics unique to the human placenta.